Optic neuritis (ON), inflammation of the optic nerve, is due to influx of autoreactive T cells and other immune cells. ON is often associated with multiple sclerosis (MS), and the transient visual impairment of ON is experienced by many patients as the initial sign of MS or as a complication later in the disease course. High dose intravenous corticosteroid therapy is considered an adequate intervention for acute exacerbations of ON, but novel therapies that can improve long-term visual outcome are in need. Decreased visual evoked potential (VEP) and electroretinogram (ERG) readings in patients indicate degeneration of the optic nerve and retinal damage, respectively, with oligodendroglial death, myelin and axonal damage, and retinal ganglion cell (RGC) death. While the mechanisms of immune dysregulation and neurodegeneration in MS and ON are still not fully characterized, studies utilizing the animal model of MS and ON, known as experimental autoimmune encephalomyelitis (EAE), have facilitated an increased understanding of the pathology underlying these diseases. Our lab has previously demonstrated increased activity and expression of calpain, a Ca2+-activated protease, in the optic nerves of EAE animals, implicating a role for calpain in the pathogenic events of ON. The roles of calpain in inflammation (T cell activation, immune cell migration), demyelination and neurodegeneration (apoptosis and axonal degeneration) are manifold. The long-term goal of this project is to assess the potential of calpain as a target for MS and ON clinical trials, in which calpain inhibition would be a novel approach to therapy. In Specific Aim 1, we hypothesize that Ca2+ influx and calpain activation will lead to axon and oligodendrocyte damage in the optic nerve and death of RGCs and other cells in the retina of animals with ON, resulting in impaired visual function. Specific Aim 2 proposes that treatment with calpain inhibitor will preserve or restore visual function by attenuating the events that lead to damage. Molecular, immunohistochemical, and electrophysiological techniques will be utilized to assess these parameters.